Myelin sheaths, which cover many nerve fibers, are composed of lipoprotein layers formed in early life. Myelin formed by the oligodendroglia in the CNS differs chemically and immunologically from that formed by the Schwann cells peripherally, but both types have the same function: to promote transmission of a neural impulse along an axon.
Many congenital metabolic disorders (eg, phenylketonuria and other aminoacidurias; Tay-Sachs, Niemann-Pick, and Gaucher's diseases; Hurler's syndrome; Krabbe's disease and other leukodystrophies) affect the developing myelin sheath, mainly in the CNS. Unless the biochemical defect can be corrected or compensated for, permanent, often widespread, neurologic deficits result.
Demyelination in later life is a feature of many neurologic disorders; it can result from damage to nerves or myelin due to local injury, ischemia, toxic agents, or metabolic disorders. Extensive myelin loss is usually followed by axonal degeneration and often by cell body degeneration, both of which may be irreversible. However, remyelination occurs in many instances, and repair, regeneration, and complete recovery of neural function can be rapid. Recovery often occurs after the segmental demyelination that characterizes many peripheral neuropathies; this process may account for the exacerbations and remissions of multiple sclerosis (MS). Central demyelination (ie, of the spinal cord, brain, or optic nerves) is the predominant finding in the primary demyelinating diseases, whose etiology is unknown. The most well known is MS. Other diseases include, for example, acute disseminated encephalomyelitis (postinfectious encephalomyelitis), adrenoleukodystrophy, adrenomyeloneuropathy, Leber's hereditary optic atrophy and related mitochondrial disorders and human T-cell lymphotropic virus (HTLV) infection-associated myelopathy.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). In pathology, the disease is characterized as scattered demyelination lesions, axonal loss and damage in both the brain and spinal cord (Lassmann, 2005), which results in a multiplicity of neurological deficits. Current therapies for managing patients with MS primarily target the inflammatory aspect of the disease (Zamvil and Steinman, 2003) and are only partly effective and limited by side effects. Recent studies suggest that glutamate-mediated cytotoxicity (excitotoxicity) (Stover et al., 1997; Barkhatova et al., 1998; Smith et al., 1999; Pitt, 2000), oxidative stress (Gilgum-Sherki et al., 2004) and mitochondrial damage (Andrews et al., 2005), may play vital roles in the pathogenesis of MS.
Remyelination is generally accepted as a regular event in MS lesions (Prineas et al., 1993; Raine et al., 1993); however, it is insufficient for myelin repair and axons remain demyelinated in MS patients (Prineas et al., 1993; Lovas et al., 2000). Possible explanations for this include failure of recruitment or survival of oligodendrocyte progenitor cells (OPCs), disturbance of differentiation/maturation of OPCs, and loss of capability of myelin forming (Wolswijk et al., 1998; Chang et al., 2003). Therefore, effective interventions for MS should not only prevent disease progression, but also promote remyelination.
Quetiapine is an atypical antipsychotic which has good efficacy and tolerability and which is useful in the treatment of schizophrenia. The use of quetiapine for the treatment of Parkinson's disease (Goldstein, 2004) and substance abuse (Brown, 2004) has also been proposed.
Atypical antipsychotic drugs (APDs), such as clozapine and quetiapine, have been widely used for treating a range of severe psychiatric disorders (Thanvi et al., 2004; Gao et al., 2005) and mental symptoms in neurological diseases (Baum et al., 2003; Bosboom et al., 2004; Altschuler et al., 2005; Carson et al., 2006). Neuroprotective effects of APDs have recently been highlighted in both in vitro and in vivo studies as new features of their therapies. In 1993, Farber and colleagues reported that the neurotoxicity produced by dizocilpine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist, in the rat retrosplenial cortex could be significantly decreased by clozapine pre-treatment (Farber et al., 1993). A subsequent study showed that olanzapine had the same effect in preventing MK-801-induced neurotoxicity (Farber et al., 1996). Other groups also reported that pre-treatment with clozapine or olanzapine blocked the neuronal vacuolization and significantly attenuated the expression of Fos-like protein in the rat retrosplenial cortex induced by dizocilpine (Fujimura et al., 2000; Hashimoto et al., 2000).
It has been demonstrated that quetiapine and olanzapine could attenuate the immobilization stress-induced decrease in the expression of BDNF in rat hippocampus (Xu et al., 2002; Luo et al., 2004), and modulate the short- and long-term behavioral consequences of chronic administration of dl-amphetamine in rats (He et al., 2005). In vitro studies also supported that the APDs clozapine, olanzapine, quetiapine, and risperidone can reduce the PC 12 cell death caused by serum withdrawal or the addition of hydrogen peroxide, β-amyloid peptide, or 1-methyl-4-phenylpyridinium (MPP+). These protective effects may be related to the regulation of expression of the low affinity NGF receptor p75 and SOD1 in PC2 cells by the drugs (Bai et al., 2002; Wei et al., 2003, Qing et al., 2003). Results from a clinical trial indicated that atypical drug treatment markedly increased the levels of plasma NGF in schizophrenia patients compared with never-treated patients or the patients treated with typical agents (Parikh et al., 2003).